GJ Churchyard

25th July 2017

Research gaps for eliminating TB deaths among people living with HIV

Overview

Research gaps for preventing TB deaths among PLWHIV Programmatic management of LTBI

Tests of infection

Short /ultra-short course regimens & durability

Treating MDR TB infection

Barriers to scaling up programmatic management of LTBI

HIV and TB co-treatment

Conclusion

more people living with HIV

dying of TB

NO

Programmatic management of LTBI

Tests of LTBI: research gaps

Current tests of infection are poorly predictive for developing active TB

Diagnostic tests that are highly predictive of development of TB disease in the near future are urgently needed

5

TST IGRA

Minimum

Optimum

30% 20%

10%

5%

3%

1%

Minimum TPP - PPV: ~6%

TST / IGRA - PPV: ~2% / ~3%

Optimum TPP - PPV: ~16%

COR

COR signature - PPV: ~7%

Positive predictive value (PPV) of COR for

South African adult population

Cumulative 2 year incidence: 2%

Effectiveness of IPT: 50%

Denkinger, Goletti et al.,

Short & ultra short course regimens & durability

Research gaps

To develop treatment regimens that are shorter and better tolerated than current short course regimens

To evaluate strategies to imporive durability of LTBI treatment in high transmission settings

6H

3HP

p3HP

A trial of 3HP as a single round or given annually in HIV-infected individuals

Part A: An observational randomised comparison of 3HP vs 6H

Primary objective

To compare treatment completion in HIV-positive participants taking 3HP to those taking 6H

6H

3HP

p3HP

Part B: A randomised controlled trial of 3HP vs p3HP

Primary objective

To compare the efficacy of two periodic (annual) rounds of 3HP (p3HP) to a single round of 3HP

6H

3HP

p3HP

Ultra-short-course TB preventive therapy in HIV-infected persons with LTBI (A5279)

Design: Phase III, individually randomised

Study population:

HIV-1 infected men and women ≥13 years old and ≥30 kg without evidence of active TB

TST/IGRA+

Live in high TB burden areas (TB prevalence ≥60/100,000/year)

Objectives: To compare the efficacy of a 4-week daily regimen of weight-based RPT/INH to 9H

Sample size: 3000 (enrolment complete)

Treating MDR TB infection

MDR TB in Household Contacts Contacts of MDR TB patients who become infected

have a high risk of progressing to active TB and possibly death

~10% of household contacts are HIV-infected

Randomized controlled trials in adult and paediatric populations are required

The potential role of new drugs with good sterilization properties should be investigated

WHO 2014 Guidelines for Preventive Therapy for MDR TB Contacts

Research Gaps

Trials of treatment for MDR TB infection

TB-CHAMP V-QUIN PHOENIX

Intervention LVF (paediatric dispersible tablet formulation) vs. placebo daily for 6 months

LVF vs placebo daily for 6 months

DLM vs INH daily for 26 weeks

Design Cluster randomized; superiority Community-based

Cluster randomized; superiority Community-based

Cluster randomized; superiority

Target Population 0-5 years of age regardless of TST or HIV status

All ages (including infants < 6 mo), TST +

1. Children 0-5 yrs, HIV +, TST/IGRA + over 5 year olds

Assumptions LVF decreases incidence from 7 to 3.5%; 80% power

LVF decreases incidence by 70% from 3% untreated; 80% power

DLM decreases incidence by 50% from 5% to 2.5%; 90% power

Sample size 788 HH 1565 contacts

1326 HH 2785 contacts

1726 HH 3452 contacts

Sites South Africa Viet Nam ACTG & IMPAACT sites

Barriers to programmatic management of LTBI

INH is cheap and effective, yet uptake of IPT for PLHIV remains low

SOURCE: 1. IPT uptake data is from the WHO TB Report, 2. PLHIV data is from UNAIDS aidsinfo.com for all countries

Cascade for LTBI treatment

Alsdurf et al., Lancet ID, 2016

Universal vs. Symptom-based TB Screening of HIV+ Pregnant Women

A Cluster-randomized Trial Baseline Characteristics by Arm

Universal Clinics (8)

N=941

Symptom Clinics (8) N=1,100

Age 30.2 yrs 29.5 yrs

Gestational age

24.6 wks 24.4 wks

TB Symptoms 17.3% 22.1%

Prior TB 9.8% 7.8%

On ART 99.5% 98.6%

CD4 count 426 cells/mm3

451 cells/mm3

Hb 11.4 g/dl 10.8 g/dl

Yield of TB diagnoses by Arm

Study Arm TB Cases

n/N Cluster-adjusted MTb Yield (95%CI)

Universal Testing 34/941 3.6% (1.2-6.0)

Symptom Testing 4/1100 0.36% (0.0-1.1)

P = 0.01

Martinson, et al. IAS 2017 TUPDB0204LB

IMPAACT4TB: Comparing health system models of 3HP delivery to increase % of

eligible PLWHIV starting 3HP

Strategies to be assessed SOC: Clinic staff training for appropriate

prescription of 3HP Opt-out prescribing; where prescription of 3HP

will be automatically included with HIV medications unless clinicians write order not to prescribe

Clinic initiated Quality improvement process .

Study design: Cluster (24+ clinics) randomized trial.

Co treatment of HIV and TB disease & infection

Modern ART, Rx of TB disease & infection & DDIs

Rifamycins likely to remain part of first line TB treatment for some time to come

Rifamycins are all potent inducers of hepatic drug metabolizing enzymes and drug transport proteins

Magnitude of induction depends on dose and frequency of dosing

High dose rifamycins may be more effective in PTB, TBM, PLWHIV with low CD4 counts

Higher-dose Rifampin and Rifapentine are promising candidates for shortened treatment regimens for DS-TB

Rifamycin based regimens recommended for treatment of LTBI 3HP (high dose isoniazid and rifapentine weekly for 3

months)

PanACEA MAMS trial; TBTC Trial 29X; Merle C. AIDS2016. RAFA Trial.; Ruslami et al. (2013) Lancet ID 13: 27

Modern ART, Rx of TB disease & infection & DDIs

Pharmacology of TAF

PG

P

PG

P

• P-glycoprotein (P-gp) is a transporter found on intestinal enterocytes (and blood-brain-barrier) • Its job is to keep foreign substances out of the body

• Inducing intestinal P-gp reduces bioavailability • Tenofovir is a P-gp substrate; Rifamycins Induce (>inhibit) P-gp

TDF=tenofovir disoproxil fumarate TAF=tenofovir alafenamide TFV-DP=tenofovir diphosphate

Adapted from http://blogs.nature.com/spoonful/files/2013/07/Res2.gif

n.b. This is what you care about How much do you need? What is the target exposure?

Pharmacology of DTG

Rifamycins induce both UGT1A1 and CYP3A4.

How much DTG do we need? What is the ‘target’ exposure?

Reese et al Drug Metab Disp (2013) 41: 353.

DTG with RIF - healthy volunteers

Dooley et al JAIDS (2013) 62: 21.

Dooley et al JAIDS (2013) 62: 21.

DTG with RBT - healthy volunteers

The INSPIRING trial: DTG- vs. EFV-based ART for TB/HIV patients taking HRZE

Design: Phase IIIb, randomized, open label trial of DTG and EFV-containing ART regimens in HIV/TB co-infected patients receiving HRZE

Arm 1: DTG (50 mg BID), plus 2NRTI

Arm 2: EFV plus 2NRTI

Duration: 48 weeks, plus open-label extension

Sample size: 125 adult patients with HIV/TB, ART-naïve; randomized 3:2

Endpoint: Proportion with HIV VL < 50 c/mL at Week 48 (snapshot)

Status: Fully enrolled, top-line results expected Q3 2017

The effect of Rif on plasma PK of FTC & TAF & intracellular TFV-DP &FTC-TP (RIFT) Trial

3HP a potential game changer WHO prioritized scaling up TB preventive therapy as part

of the End TB Strategy

3HP a potential “game changer” for TB prevention in HBCs

Shorter

Less toxic

Better adherence

Higher barrier to resistance

At least similar efficacy

Less burden to health programmes to implement

Safe with EFV-based regimens

DTG with once-weekly HP: healthy volunteers (n=4)

Brooks et al CROI 2017 Poster 409A

Total number of HP doses: 3

Participant Tolerability

1 Nausea, vomiting, headache, fever with Dose #3 of HP Symptom resolution by 72 hours post-dose Transaminase elevations 72 hours post-dose

2 Tolerated regimen

3 Withdrew prior to 3rd dose (family/work obligations)

4 Nausea, vomiting, fever, orthostatic hypotension with Dose #3 of HP Transaminase elevations 24 hours post-dose Symptom resolution by 72 hours post-dose

DTG with once-weekly HP: healthy volunteers (n=4)

Study terminated early because of AE in two healthy volunteers

Brooks et al CROI 2017 Poster 409A

Impact of HP on DTG concentrations

HP dosing: Days 5, 12, 19

Days after an HP dose: 0 2 3 6 7 1

Brooks et al CROI 2017 Poster 409A

Primary Objectives:

To evaluate effect of RPT & INH on DTG PK

To assess the safety of 3HP given with DTG

Secondary Objectives

To determine optimal DTG dose with 3HP

To estimate % maintaining virologic suppression

To describe the PK of INH & RPT with DTG

IMPAACT4TB: DTG and 3HP in PLWHIV Objectives

Implications for 3HP implementation

If safe and no or minimal PK interaction 3HP can continue to be scaled up for PLWHIV

If PK issue, DTG dose can be adjusted

3HP remains an option for household contacts

Could INH/CTX FDC be an alternative to 3HP for PLWHIV if there is a serious safety concern?

Use of RIFAMYCINS with DTG or TAF Indication Rifamycin,

Dose ‘DDI’ Trials, ART, TB drugs Study population

Results expected

Latent TB Infection

Once-weekly Rifapentine (900 mg, as 3HP)

NIH Clinical Centers (NCT02771249)

DTG 50 mg QD, DRV/Co 800/150 mg QD Healthy volunteers

CROI 2017, poster 409A Study of DTG with RPT/INH in PLWHIV planned No studies of TAF with 3HP

TB Disease Daily standard-dose rifampin (10 mg/kg daily)

INSPIRING EFV, DTG 50 mg BID + HRZE HIV/TB co-infection

RADIO DTG 50 or 100 mg QD + RIF

Healthy volunteers

RIFT TAF/FTC + RIF only Healthy volunteers

Q3 2017 (24-week results) Q4 2017 (HV, PLWHIV to follow) Q4 2017 (HV, PLWHIV to follow)

High-dose rifampin (20-35 mg/kg daily)

Rifavirenz EFV 600 or 800 + HRZE HIV/TB co-infection

No studies of DTG or TAF with high dose RIF

High-dose Rifapentine (1200 mg daily)

TBTC 31/ACTG 5349 EFV + HPZE or HPZM HIV/TB co-infection

Study of DTG or TAF with high dose RPT proposed

Conclusion

PLHIV are at high risk of developing TB

HIV associated TB is associated with worse outcomes

Research is required to address knowledge gaps to Step up the TB/HIV response Research to optimize HIV/TB co-treatment of TB

disease and infection is a high priority

Acknowledgements

Kelly Dolley

Richard Chaisson

Mark Hatherill

PHOENIx team

Design: Single-arm Phase I/II PK and safety study

Regimens: Group 1A: DTG 50mg daily + TDF/FTC +3HP (900/900) interim analysis

Group 1B and 2: DTG, dose TBD, + TDF/FTC + 3HP

Duration: 8 weeks DTG+TDF/FTC (EFV washout)

12 weeks DTG+TDF/FTC+HP

post-treatment DTG access 12 months

Sample size: 60 (30 in Group 1 (12 in 1A, 18 in 1B), 30 in Group 2)

IMPAACT4TB: DTG and 3HP in PLWHIV Proposed Study design

Bedaquiline Overview

Is an oral diarylquinoline MOA: inhibits ATP synthase Active against replicating & non-replicating

MTB Resistance

Spontaneous mutations: 1 x 107 to 108 Up regulation of efflux pumps Cross resistance with clofazamine High barrier to resistance

99.9% protein bound Terminal half life of ~6 months

Bedaquiline Practice

WHO recommends BDQ for 6 months for treatment of Pre-XDR TB

XDR TB

MDR TB with intolerance to other drugs

BDQ may be used to substitute for SLID

BDQ may be used with caution with renal dysfunction/failure

Bedaquiline Use with ARTs

Metabolized by CYP3A to M2 metabolite

BDQ levels reduced by ~50% with efavirenz

BDQ levels increased by 28% with LPV/r

BDQ can be combined with 2 NRTIs & NVP or LPV/r, integrase inhibitors

Delamanid Overview

Is an oral nitroimidazole Inhibits mycolic acid synthesis & releases NO within

MTB Active against replicating & non-replicating bacilli Resistance

May be due to mutations in nitroreductase gene or genes involved in F420 synthesis or activation

Spontaneous mutations occur in 1 x 105 to 106

Low barrier to developing resistance

Highly protein bound (>99.5%) Metabolised by albumin Half-life: DLM-34 hrs, DM-6705>150 hours

Delamanid Practice

DLM has low bioavailability and should be given with food

DLM must be taken separately from other treatment Requires twice daily dosing (100mg BD)

Once daily dosing during maintenance phase being studied

DLM recommended for 24 weeks Recommended novel drug for

Children (Otsuka 233 PK study in children 0-6+ yrs nearing completion)

Efavirenz based ART regimen Patients with prior clofazamine exposure

Delamanid Use with ARTs

DLM levels not affected by co-administration with Effavirenz

LPV/r may increase DLM concentration